Radiotherapy is an efficient method of treating cancers albeit often resulting in varying outcomes. It is abundantly clear that cells vary in their response to ionizing radiation induced DNA damage depending on their cell type, differentiation status, proliferation state and cell cycle stage etc. Normal stem cells exhibit a radiosensitive phenotype contributing to acute and chronic sequelae of normal tissue injury following radiotherapy, but differentiated cells display a loss of function of apoptosis and are radioresistant. Most of the research has focused primarily on radiosensitization of tumor and less on radioprotection of normal tissues. Therefore, an improved understanding of differential radiation responses in varying cellular contexts is imperative for efficient treatment and management of malignancies by radiotherapy. Cellular response to DNA damage depends on the combination of complex and sophisticated networks of DNA damage response signals that monitor/ maintain genome integrity and cell death signaling pathways that eliminate damaged cells. The goal of this research is to characterize the role of phospho protein phosphatase- 2A (PP2A) in regulation of radiosensitivity of normal stem cells. Specifically, a multifaceted approach has been proposed to unravel the novel associations between cellular differentiation, DNA damage response and apoptotic response. Utilizing the normal stem cell tissue niches in vivo, as well as isogenic primary cell culture models of normal stem and differentiated cells, molecular basis of stem cell radiosensitivity and the dual role of PP2A in inhibiting DNA damage response and promoting apoptotic response in normal stem cells will be delineated along with determining the validity of PP2A is a molecular target for development of novel radioprotective drugs. This insight into the molecular switches and signal transduction networks unique to stem cells that are different from the differentiated progeny cells would be crucial for developing therapeutic prevention and intervention strategies to effectively minimize the stem cell drop-out associated with undesired side effects of radiotherapy which impairs the quality of life of cancer survivors especially in the pediatric neoplasms.